RNF111/Arkadia is a SUMO-targeted ubiquitin ligase that facilitates the DNA damage response |
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Authors: | Sara L. Poulsen Rebecca K. Hansen Sebastian A. Wagner Loes van Cuijk Gijsbert J. van Belle Werner Streicher Mats Wikstr?m Chunaram Choudhary Adriaan B. Houtsmuller Jurgen A. Marteijn Simon Bekker-Jensen Niels Mailand |
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Affiliation: | 1.Ubiquitin Signaling Group, Department of Disease Biology, 2.Department of Proteomics, and 3.Protein Function and Interactions Group, The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, DK-2200 Copenhagen, Denmark;4.Department of Genetics, and 5.Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Center, 3015 GE Rotterdam, Netherlands |
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Abstract: | Protein modifications by ubiquitin and small ubiquitin-like modifier (SUMO) play key roles in cellular signaling pathways. SUMO-targeted ubiquitin ligases (STUbLs) directly couple these modifications by selectively recognizing SUMOylated target proteins through SUMO-interacting motifs (SIMs), promoting their K48-linked ubiquitylation and degradation. Only a single mammalian STUbL, RNF4, has been identified. We show that human RNF111/Arkadia is a new STUbL, which used three adjacent SIMs for specific recognition of poly-SUMO2/3 chains, and used Ubc13–Mms2 as a cognate E2 enzyme to promote nonproteolytic, K63-linked ubiquitylation of SUMOylated target proteins. We demonstrate that RNF111 promoted ubiquitylation of SUMOylated XPC (xeroderma pigmentosum C) protein, a central DNA damage recognition factor in nucleotide excision repair (NER) extensively regulated by ultraviolet (UV)-induced SUMOylation and ubiquitylation. Moreover, we show that RNF111 facilitated NER by regulating the recruitment of XPC to UV-damaged DNA. Our findings establish RNF111 as a new STUbL that directly links nonproteolytic ubiquitylation and SUMOylation in the DNA damage response. |
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